US6713089B1ExpiredUtility

Quick release pharmaceutical compositions of drug substances

Assignee: NYCOMED DANMARK ASPriority: Sep 10, 1998Filed: Sep 10, 1999Granted: Mar 30, 2004

Est. expirySep 10, 2018(expired)· nominal 20-yr term from priority

Inventors:Poul Egon Bertelsen Niels Gjørløv Hansen Hermann Ruckendorfer Shigeru Itai

A61P 43/00A61P 5/46A61P 29/00A61P 25/04A61P 25/24A61K 9/2009A61P 1/04A61K 9/1611

PatentIndex Score

138

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References

Claims

Abstract

The present invention relates to an oral modified release pharmaceutical composition for the administration of a therapeutically and/or prophylactically effective amount of an active substance (a drug substance), to obtain a relatively fast or quick onset of the therapeutic and/or prophylactic effect. The drug substances contained in a modified release pharmaceutical composition according to the invention are suitably a drug substance which has a pKa value below about 5, such as in a range of from about 4 to about 5. The composition is based on a powder comprising a therapeutically and/or prophylactically active substance and has such a particle size that: when the powder is subjected to a sieve analysis, then at least about 90% w/w of the particles pass through a 180 micron sieve, and when the powder is contacted with an aqueous medium to form a particulate composition, which as such a particle size that when the particulate composition is subjected to a sieve analysis, then at least about 50% w/w of the particles passes through a 180 micron sieve. Further more, the composition, when tested in accordance with the dissolution method (I) defines herein, employing 0.07 HCl as dissolution medium, release at least about 50% w/w of the active substance within the first 20 minutes of the test.

Claims

exact text as granted — not AI-modified

What is claimed is:

1. A quick release pharmaceutical composition for oral administration comprising a therapeutically and/or prophylactically active substance and at least one pharmaceutically acceptable excipient, said active substance being defined by one of features i) or ii):
i) the active substance has a solubility which does not exceed 0.1% w/v in 0.1 N hydrochloric acid at room temperature;
ii) the active substance has a pK a value which does not exceed 5.5,
wherein the quick release pharmaceutical composition is in the form of a particulate composition or being based on a particulate composition, the particulate composition contains the active substance in contact with an alkaline substance and further comprises one of features iii) or iv):
iii) the particulate composition is based on a powder comprising the therapeutically and/or prophylactically active substance, wherein said powder has a particle size such that when the powder is subjected to a sieve analysis, then at least 90% w/w of the particles pass through sieve 180 μm, and wherein when the powder is being contacted with an aqueous medium to form a particulate composition, the particle size of the particulate composition when subjected to a sieve analysis, is such that at least 50% w/w of the particles pass through sieve 180 μm;
iv) the particulate composition is obtained by contacting a powder that comprises the therapeutically and/or prophylactically active substance and has a particle size such that when the powder is subjected to a sieve analysis then at least 90% w/w of the particles pass through sieve 180 μm with an aqueous medium in such a manner that the mean particle size of the particles of the particulate composition is not greater than 100% larger than the mean particle size of the powder before being contacted with the aqueous medium,
and wherein the quick release pharmaceutical composition, when tested in accordance with the dissolution method I defined herein employing 0.07 N hydrochloric acid as dissolution medium, dissolves at least 50% w/w of the active substance within the first 20 minutes of the test.

2. The composition according to claim 1 , wherein the composition when subjected to dissolution method I as defined herein employing 0.07 N hydrochloric acid as dissolution medium, dissolves at least 55% w/w of total amount of active substance present in the composition within the first 20 minutes of the test.

3. The composition according to claim 1 , wherein the solubility of the therapeutically and/or prophylactically active substance in 0.1 N hydrochloric acid at room temperature does not exceed 0.05% w/v.

4. The composition according to claim 1 , wherein the therapeutically and/or prophylactically active substance when tested by solubility method I described herein has a dissolution rate such that it allows an amount equal to or less than 50% w/w of the active substance to be dissolved within the first 20 min of the test.

5. The composition according to claim 1 , wherein the composition is in the form of a solid composition.

6. The composition according to claim 1 , wherein the composition is in the form of a particulate composition.

7. The composition according to claim 1 , in the form of a unit dosage form.

8. The composition according to claim 1 , wherein the aqueous medium comprises water and an organic solvent.

9. The composition according to claim 1 , wherein the mean particle size of the particles of the particulate composition is less than or equal to 250 μm after contact with an aqueous medium.

10. The composition according to claim 1 , wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of binders, disintegrants, fillers and diluents.

11. The composition according to claim 1 , comprising a filler having binding properties.

12. The composition according to claim 11 , wherein the filler having binding properties is selected from the group consisting of lactose, sugar derivatives, calcium carbonate (CaCO 3 ), tricalcium phosphate (Ca 3 (PO 4 ) 2 ), calcium hydrogen phosphate (CaHPO 4 ), and/or mixtures thereof.

13. The composition according to claim 11 , wherein the filler having binding properties is calcium hydrogen phosphate.

14. The composition according to claim 11 , wherein the filler having binding properties as raw material has a mean particle size which does not exceed 140 μm.

15. The composition according to claim 1 , wherein the alkaline substance is an antacid or an antacid-like substance.

16. The composition according to claim 15 , wherein the alkaline substance is an antacid or an antacid-like substance selected from the group consisting of sodium hydrogen carbonate, magnesium carbonate, magnesium hydroxide, magnesium metasilicate aluminate and mixtures thereof.

17. The composition according to claim 15 , wherein the mean particle size of the antacid-like substance as raw material does not exceed 250 μm.

18. The composition according to claim 1 , wherein a particulate composition further has been processed to obtain a composition in the form of tablets, capsules or sachets.

19. The composition according to claim 1 , in the form of tablets.

20. The composition according to claim 18 , wherein the composition has a mechanical strength such as to enable handling and coating in a conventional coating apparatus.

21. The composition according to claim 20 , wherein the composition when subjected to a crushing strength test in accordance with Ph. Eur., has a crushing strength of about 50 N to about 150 N.

22. The composition according to claim 1 , wherein the therapeutically and/or prophylactically active substance is a non-steroid anti-inflammatory drug substance (NSAID substance).

23. The composition according to claim 1 , wherein the therapeutically and/or prophylactically active substance is selected from the group consisting of lornoxicam, diclofenac, nimesulide, ibuprofen, piroxicam, piroxicam (betacyclodextrin), naproxen, ketoprofen, tenoxicam, aceclofenac, indometacin, nabumetone, acemetacin, morniflurnate, meloxicam, flurbiprofen, tiaprofenic acid, proglumetacin, mefenamic acid, fenbufen, etodolac, tolfenamic acid, sulindac, phenylbutazone, fenoprofen, tolmetin, acetylsalicylic acid, dexibuprofen, paracetamol, and pharmaceutically acceptable salts, complexes and/or prodrugs thereof and mixtures thereof.

24. The composition according to claim 1 , wherein the therapeutically and/or prophylactically active substance is lornoxicam or a pharmaccutically acceptable salt, complex or prodrug thereof.

25. The composition according to claim 1 , comprising a further active drug substance.

26. The composition according to claim 25 , wherein the further active drug substance is an antidepressant, an opioid, a prostaglandine analogue (such as misoprostol), a glucocorticosteroid, a cytostaticum (such as methotrexate), a H 2 receptor antagonist (such as cimetidine, ranitidine), a proton pump inhibitor (such as pantoprazole, omeprazole, lansoprazole) and/or an antacidum.

27. The composition according to claim 25 , wherein the further active drug substance is paracetamol, penicillamine, sulfasalazine and/or auranorfin.

28. The composition according to claim 1 in unit dosage form comprising from 1 to 32 mg of the therapeutically and/or prophylactically active substance.

29. The composition according to claim 1 in unit dosage form comprising from 1 mg to 1.6 g of the therapeutically and/or prophylactically active substance.

30. The composition according to claim 1 in unit dosage form comprising from 50 mg to 1.1 g of the therapeutically and/or prophylactically active substance.

31. The composition according to claim 1 in unit dosage form comprising from 100 mg to 1.0 g of the therapeutically and/or prophylactically active substance.

32. The composition according to claim 1 in unit dosage form comprising from 200 mg to 900 mg of the therapeutically and/or prophylactically active substance.

33. The composition according to claim 1 in unit dosage form comprising from 300 mg to 800 mg of the therapeutically and/or prophylactically active substance.

34. The composition according to claim 1 , wherein the therapeutically and/or prophylactically active substance is lornoxicam and a unit dosage of the composition contains 4, 8, 12, 16, 20, 24, 28, 32 or 36 mg of lornoxicam.

35. The composition according to claim 1 , wherein the water content in the composition does not exceed 5% w/w as determined by the LOD (loss on drying) method described herein.

36. The composition according to claim 1 , comprising sodium hydrogen carbonate.

37. The composition according to claim 1 , comprising calcium hydrogen phosphate.

38. The composition according to claim 1 , coated with a coating which does not substantially retard the release of the therapeutically and/or prophylactically active substance from the composition.

39. The composition according to claim 1 , coated with a film coating.

40. A method for the preparation of a composition as defined in claim 1 , the method comprising
i) mixing the therapeutically and/or prophylactically active substance with a) an alkaline substance, b) a filler having binding properties, and, optionally, c) other pharmaceutically acceptable excipients to obtain a powder mixture,
ii) contacting the thus obtained powder mixture with an aqueous medium to obtain a wet powder,
iii) drying the thus obtained wet powder at a temperature above room temperature until the water content in the powder is at the most 5% w/w determined as described herein, to obtain a first particulate mixture,
iv) sieving the thus obtained first particulate mixture,
v) optionally, adding any further pharmaceutically acceptable excipients to obtain a second particulate mixture,
vi) optionally, compressing the thus obtained second particulate mixture into tablets, and
vii) optionally, coating the thus obtained tablets.

41. The method according to claim 40 , wherein step ii) is performed in a suitable apparatus which enables an energy input which is sufficient to bringing the particles in contact with the aqueous medium without substantially deteriorate the stability of the final composition.

42. The method according to claim 40 , wherein step ii) is performed in a suitable apparatus which enables an energy input which is sufficient to bringing the therapeutically and/or prophylactically active substance and the alkaline substance in contact with the aqueous medium without negatively influencing the release rate of the active substance from the final composition.

43. The method according to claim 41 , wherein the energy input is provided in a discontinuous manner.

44. The method according to claim 40 , wherein step ii) is performed in intervals of wet-massing and wet-resting.

45. The method according to claim 40 , wherein the alkaline substance employed in step i) is an antacid-like substance such as sodium hydrogen carbonate, magnesium carbonate, magnesium hydroxide or magnesium metasilicate aluminate or mixtures thereof.

46. The method according to claim 40 , wherein the filler having binding properties is selected from the group consisting of lactose, sugar derivatives, calcium carbonate (CaCO 3 ), tricalcium phosphate (Ca 3 (PO 4 ) 2 ), calcium hydrogen phosphate (CaHPO 4 ), and/or mixtures thereof.

47. The method according to claim 40 , wherein the aqueous medium employed in step ii) is a solvent comprising water and an organic solvent.

48. The method according to claim 47 , wherein the organic solvent is a solvent which is miscible with water such as a branched or unbranched lower (C 1 -C 5 ) aliphatic alcohol like, ethanol, methanol, isopropanol, 1-propanol, 1-butanol, 2-butanol, iso-butanol, tert. butanol and 1-pentanol, 2-pentanol, 3-pentanol, iso-pentanol and tert. pentanol and mixtures thereof.

49. The method according to claim 48 , wherein the concentration of the organic solvent in the solvent ranges from 0% v/v to 95% v/v.

50. The method according to claim 40 , wherein step ii) is performed in a conventional high shear mixer employing an energy input which is sufficient to enable a contact to take place between the therapeutically and/or prophylactically active substance and the alkaline substance employed in step i) but at the same time is sufficiently low to avoid formation of a large amount of agglomerates during the mixing.

51. The method according to claim 40 , wherein the mean particle size of the particles of the first particulate mixture is not greater than 100% larger than the mean particle size of the powder mixture from step i) before subjecting the powder mixture to the reaction in the aqueous medium employed in step ii).

52. The method according to claim 51 , wherein the mean particle size of the particle of the first particulate mixture is not greater than 90% larger than the mean particle size of the powder mixture from step i) before subjecting the powder mixture to the reaction in an aqueous medium employed in step ii).

53. The method according to claim 40 , wherein the powder obtained in step i) has a particle size such that when the powder is subjected to a sieve analysis, at least 90% w/w of the particles pass through sieve 180 μm, and the first particulate mixture obtained in step iii) has a particle size such that when the particulate composition is subjected to a sieve analysis, at least 50% w/w of the particles pass through sieve 180 μm.

54. The method according to claim 40 , wherein the mean particle size of the particles of the first particulate mixture does not exceed 250 μm.

55. A method for treatment and/or prophylaxis of acute pain and/or mild or moderate pain comprising administering to a patient an effective amount of a therapeutically and/or prophylactically active substance in the form of a quick release composition, said active substance being defined by one of features i) or ii):
i) the active substance has a solubility which does not exceed 0.1% w/v in 0.1 N hydrochloric acid at room temperature;
ii) the active substance has a pK a value which does not exceed 5.5,
and wherein the quick release pharmaceutical composition is in the form of a particulate composition or being based on a particulate composition, the particulate composition contains the active substance in contact with an alkaline substance and further has one of features iii) or iv):
iii) the particulate composition is based on a powder comprising the therapeutically and/or prophylactically active substance, wherein said powder has a particle size such that when the powder is subjected to a sieve analysis, at least 90% w/w of the particles pass through sieve 180 μm, and wherein when the powder is being contacted with an aqueous medium to form a particulate composition, the particle size of the particulate composition, when subjected to a sieve analysis, is such that at least 50% w/w of the particles pass through sieve 180 μm;
iv) the particulate composition is in the form of a particulate composition or being based on a particulate composition which is obtained by contacting a powder that comprises the therapeutically and/or prophylactically active substance and has a particle size such that when the powder is subjected to a sieve analysis then at least 90% w/w of the particles pass through sieve 180 μm with an aqueous medium in a manner such that the mean particle size of the particles of the particulate composition is not greater than 100% larger than the mean particle size of the powder before being contacted with the aqueous medium,
and wherein the quick release pharmaceutical composition, when tested in accordance with the dissolution method I defined herein employing 0.07 N hydrochloric acid as dissolution medium, dissolves at least 50% w/w of the active substance within the first 20 minutes of the test.

56. A method for fast relief of acute pain comprising administering to a patient in need thereof an effective amount of a therapeutically and/or prophylactically active substance in the form of a quick release composition, said active substance being defined by one of features i) or ii):
i) the active substance has a solubility which does not exceed 0.1% w/v in 0.1 N hydrochloric acid at room temperature;
ii) the active substance has a pK a value which does not exceed 5.5,
and wherein the quick release pharmaceutical composition is in the form of a particulate composition or being based on a particulate composition, the particulate composition contains the active substance in contact with an alkaline substance and further has one of features iii) or iv):
iii) the particulate composition is based on a powder comprising the therapeutically and/or prophylactically active substance, wherein said powder has a particle size such that when the powder is subjected to a sieve analysis, at least 90% w/w of the particles pass through sieve 180 μm, and wherein when the powder is being contacted with an aqueous medium to form a particulate composition, the particle size of the particulate composition, when subjected to a sieve analysis, is such that at least 50% w/w of the particles pass through sieve 180 μm;
iv) the particulate composition is in the form of a particulate composition or being based on a particulate composition which is obtained by contacting a powder that comprises the therapeutically and/or prophylactically active substance and has a particle size such that when the powder is subjected to a sieve analysis then at least 90% w/w of the particles pass through sieve 180 μm with an aqueous medium in such a manner that the mean particle size of the particles of the particulate composition is not greater than 100% larger than the mean particle size of the powder before being contacted with the aqueous medium,
and wherein the quick release pharmaceutical composition, when tested in accordance with the dissolution method I defined herein employing 0.07 N hydrochloric acid as dissolution medium, dissolves at least 50% w/w of the active substance within the first 20 minutes of the test.

57. The composition according to claim 1 , wherein the active substance has a pK a value which does not exceed 5.3.

58. The composition according to claim 1 , wherein the active substance has a pK a value in the range of from 3.4 to 5.0.

59. The composition according to claim 1 , wherein the quick release pharmaceutical composition is based on a powder comprising the therapeutically and/or propylactically active substance and having a particle size such that when the powder is subjected to a sieve analysis, at least 92% of the particles pass through sieve 180 μm.

60. The composition according to claim 1 , wherein when the powder being contacted with an aqueous medium to form a particulate composition, which has a particle size such that when the particulate composition is subjected to a sieve analysis, at least 55% w/w of the particulate composition pass through sieve 180 μm, when subjected to a sieve analysis.

61. The method according to claim 42 , wherein the energy input is provided in a discontinuous manner.

62. The method according to claim 55 , wherein the composition conforms to any one of claims 1 to 39 and 57 to 60 .

63. The method according to claim 56 , wherein the composition conforms to any one of claims 1 to 39 and 57 to 60 .

64. The composition according to claim 11 wherein the sugar derivatives are selected from the group consisting of mannitol and sorbitol.

65. The composition according to claim 29 , wherein the unit dosage form comprises from 1 mg to 1.2 g of the therapeutically and/or prophylactically active substance.

66. The method according to claim 46 wherein the sugar derivatives are selected from the group consisting of mannitol and sorbitol.

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